UK-2A, B, C and D, Novel Antifungal Antibiotics from Streptomyces sp. 517-02 VI(2). Structure-activity Relationships of UK-2A.

Usuki, Yoshinosuke; Gotō, Kunio; Kiso, Tetsuo; Tani, Kazunori; Xu, Ping; Fujita, Ken‐ichi; Iio, Hideo; Taniguchi, Makoto

doi:10.7164/antibiotics.55.607

Cited by 13 publications

(8 citation statements)

References 12 publications

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“…Yeast and filamentous fungi represented 10.3% of the latter. These results confirm that the actinomycetes are able to produce a wide variety of antibiotics with antifungal activity (Asolkar et al, 2002;Usuki et al, 2002). A general analysis of the results (Table 2) points to a higher recovery of actinomycetes in NGB and HC samples.…”

Section: Resultssupporting

confidence: 67%

Antifungal activity of actinomycetes from cuban soils

Iznaga

Lemus

González

et al. 2004

Phytotherapy Research

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This study reports on the capacity of actinomycete strains isolated from Cuban soils to produce antifungal agents. The antimicrobial activities were determined by susceptibility disk assay methods. We isolated 563 different actinomycetes and 286 produced compounds with antifungal activity. Our screening method indicated the presence of many possible polyene macrolide antibiotics and the important antifungal activity in the soils rich in minerals.

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Section: Resultssupporting

confidence: 67%

Antifungal activity of actinomycetes from cuban soils

Iznaga

Lemus

González

et al. 2004

Phytotherapy Research

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“…While the development of fenpicoxamid as a fungicide for the cereals market validates the fermentation product itself as an effective antifungal entity, several efforts have undertaken semi‐synthetic modification of UK‐2A in pursuit of further activity enhancements. In this regard, we recently described the effects on antifungal activity of modifications to, or replacement of, the picolinic acid moiety with 19 arylcarboxylates, extending the earlier efforts of Usuki et al These latter authors also explored mimicking the antimycin A macrocycle in a ‘modified UK‐2A’ by replacement of the benzyl and isobutyryl ester groups at positions 8 and 7, respectively, with n ‐butyl and 3‐Me‐butyryl substituents both independently and simultaneously . Although no antifungal data were presented, these changes had minimal impact on potency as respiratory inhibitors, indicating some tolerance for structural modification in these positions.…”

Section: Introductionmentioning

confidence: 98%

Synthesis and biological activity of analogs of the antifungal antibiotic UK‐2A. II. Impact of modifications to the macrocycle benzyl position

Owen

Meyer

Slanec

et al. 2019

Pest Management Science

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BACKGROUND: UK-2A is an antifungal antibiotic produced by Streptomyces sp. 517-02. Derivatization of its picolinamide OH to form the isobutyryl acetal led to the discovery of fenpicoxamid (InatreqTM active), which is currently under development as a fungicide by Dow AgroSciences LLC. This paper documents efforts to achieve additional efficacy enhancements through semi-synthetic modification of the benzyl substituent of the UK-2A macrocycle.RESULTS: Of 34 analogs prepared, the most active had mitochondrial electron transport IC 50 values 1.5-to 3.7-fold higher than UK-2A (IC 50 0.86 nM). The cyclohexyl analog (38, IC 50 1.23 nM) was the most intrinsically active derivative, and inhibited in vitro growth of Zymoseptoria tritici (EC 50 2.8 ppb) and Leptosphaeria nodorum (EC 50 6.2 ppb) more strongly than UK-2A (EC 50 5.3 and 11.3 ppb for Z. tritici and L. nodorum, respectively). Heterocyclic ring systems and polar linker functionalities resulted in substantial activity loss . Several analogs (20, 22, 23, 24, 36 and 38) translated Z. tritici in vitro growth inhibition activity to in planta disease control more effectively than did UK-2A, with log D being a key factor in this regard. CONCLUSIONS: UK-2A is amenable to further modification at the benzyl position on the macrocycle, which provides opportunities for manipulation of physical properties while retaining strong intrinsic and antifungal activity.

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“…UK‐2A presents several structural features amenable to semi‐synthetic modification, notably the isobutyryl ester and benzyl substituents at positions 7 and 8, respectively, of the bislactone ring as well as the picolinamide ring attached at C3 via the amide linkage. Previous structure–activity relationship (SAR) studies established that both the picolinamide 3‐OH group of UK‐2A and the stereochemistry at C3 of the bislactone macrocycle, the point of attachment of the amide linker, are structural features critical for inhibitory potency. Methylation of the former eliminated biological activity while the R ‐epimer at C3 was some 40–50‐fold less potent than the natural S ‐epimer (shown in Fig.…”

Section: Introductionmentioning

confidence: 99%